Interleukin-6 expression contributes to lapatinib resistance through maintenance of stemness property in HER2-positive breast cancer cells

// Wei-Chien Huang 1, 2, 3, 4 , Chao-Ming Hung 5, 6 , Ching-Ting Wei 5, 6, * , Tsung-Ming Chen 7, * , Pei-Hsuan Chien 8 , Hsiao-Lin Pan 5 , Yueh-Ming Lin 9 , Yun-Ju Chen 5, 8, 10 1 The Ph.D. program for Cancer Biology and Drug Discovery, China Medical University and Academia Sinica, Taichung 404, Taiwan 2 Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan 3 Center for Molecular Medicine, China Medical University and Hospital, Taichung 404, Taiwan 4 Department of Biotechnology, Asia University, Taichung 413, Taiwan 5 School of Medicine for International Students, I-Shou University, Kaohsiung 824, Taiwan 6 Department of General Surgery, E-Da Hospital, Kaohsiung 824, Taiwan 7 Department and Graduate Institute of Aquaculture, National Kaohsiung Marine University, Kaohsiung 811, Taiwan 8 Department of Medical Research, E-Da Hospital, Kaohsiung 824, Taiwan 9 Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan 10 Department of Biological Science & Technology, I-Shou University, Kaohsiung 824, Taiwan * These authors have contributed equally to this work Correspondence to: Yun-Ju Chen, email: yjchen0326@isu.edu.tw Keywords: lapatinib, interleukin-6, HER2, resistance, breast cancer Received: February 10, 2016      Accepted: August 09, 2016      Published: August 22, 2016 ABSTRACT Lapatinib is an inhibitor of human epidermal growth factor receptor 2 (HER2), which is overexpressed in 20-25% of breast cancers. Clinically, lapatinib has shown promising benefits for HER2-positive breast cancer patients; however, patients eventually acquire resistance, limiting its long-term use. In a previous study, we found that interleukin-6 (IL-6) production was increased in acquired lapatinib-resistant HER2-positive breast cancer cells. In the present study, we confirmed that lapatinib-resistant cells had elevated IL-6 expression and also maintained both stemness population and property. The increase in IL-6 was required for stemness property maintenance, which was mediated primarily through the activation of signal transducer and activator of transcription 3 (STAT3). Blocking IL-6 activity reduced spheroid formation, cell viability and subsequently overcame lapatinib resistance, whereas stimulation of IL-6 rendered parental cells more resistant to lapatinib-induced cytotoxicity. These results point to a novel mechanism underlying lapatinib resistance and provide a potential strategy to overcome resistance via IL-6 inhibition.